Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1%–2% of the population over the age of 65. As the population ages, it is anticipated that the burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves the quality of life of many PD patients, there are no treatments that can slow down, halt, or reverse disease progression. Because the loss of a specific cell type, midbrain dopamine neurons in the substantia nigra, is the main cause of motor dysfunction in PD, it is considered a promising target for cell replacement therapy. Indeed, numerous preclinical and clinical studies using fetal cell transplantation have provided proof of concept that cell replacement therapy may be a viable therapeutic approach for PD. However, the use of human fetal cells remains fraught with controversy due to fundamental ethical, practical, and clinical limitations. Groundbreaking work on human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells, coupled with extensive basic research in the stem cell field offers promising potential for hPSC-based cell replacement to become a realistic treatment regimen for PD once several major issues can be successfully addressed. In this review, we will discuss the prospects and challenges of hPSC-based cell therapy for PD.

Emergence of glycogen synthase kinase-3 interaction domain enhances phosphorylation of SARS-CoV-2 nucleocapsid protein

A structural protein of SARS-CoV-2, nucleocapsid (N) protein is abundantly expressed during viral replication. The N protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3{beta} constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), commonly found in many endogenous GSK-3{beta} binding proteins, such as Axins, FRATs, WWOX and GSKIP. Indeed, N interacts with GSK-3{beta} similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. Unlike with endogenous GID proteins, the N interaction neither disturbs endogenous GSK-3 activity nor regulates subsequent canonical Wnt activity and the Snail-EMT program. Notably, N abundance in SARS-CoV-2 is incomparably high compared to other coronaviruses, such as 229E, OC43 and HKU1. Compared to other coronaviruses, N harbors a CDK1 primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3{beta}. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allows increased abundance and hyper-phosphorylation of N. Our observations suggest that the emergence of GID and mutations for increased phosphorylation in N may have contributed to the emergence of SARS-CoV-2 and evolution of variants, respectively. Further study, especially in a BSL3-equipped facility, is required to elucidate the functional importance of GID and N phosphorylation in SARS-CoV-2 and variants.

Synovial Hemangioma Mimicking a Meniscal Cyst of the Knee / 대한정형외과학회잡지

Synovial hemangioma is a vascular malformation that usually involves the knee. This paper presents the diagnostic ultrasound findings of a synovial hemangioma that could be mistaken for a medial meniscus cyst in a 37-year-old man and report the clinical result of the meniscal repair after an open excision.

Apurinic/apyrimidinic endonuclease 1 is associated with poor prognosis after curative resection followed by adjuvant chemotherapy in patients with stage III colon cancer

Purpose@#Apurinic/apyrimidinic endonuclease 1 (APE1) is a key enzyme involved in the base excision repair pathway. It also has redox activity and maintains various transcription factors in an active reduced state. APE1 may be associated with chemoresistance. In the present study, we first investigated the expression level of APE1 protein and its correlation with oncologic outcomes of oxaliplatin-based chemotherapy in patients with stage III colon cancer. Further, we investigated the effects of human APE1 siRNA on the sensitivity of oxaliplatin in SNU-C2A colon cancer cells. @*Methods@#Tissue specimens from tumor and normal colon of 33 patients with stage III colon cancer were obtained from 2006 to 2009. The patients received at least eight cycles of oxaliplatin-based chemotherapy. APE1 expression was analyzed by immunohistochemistry and Western blotting using a cultured SNU-C2A cell line. Cell viability and apoptosis were determined by Cell Counting Kit-8 and caspase-3 cleavage using Western blotting. @*Results@#All the colon cancer tissues showed APE1 staining in the nucleus, whereas all the normal colon tissues were negative for APE1 staining in the cytoplasm. The group with a higher expression of APE1 demonstrated poorer prognosis than the group with low expression (P=0.026 for overall survival and P=0.021 for disease-free survival). Treatment with oxaliplatin resulted in a dose-dependent increase in APE1 expression in SNU-C2A cells. APE1 siRNA significantly enhanced oxaliplatin-induced growth inhibition, and also increased oxaliplatin-induced apoptosis in SNU-C2A cells. @*Conclusion@#APE1 could be considered a prognostic factor in colon cancer patients treated with oxaliplatin-based chemotherapy.

Ascending Colon Cancer with Pathologically Confirmed Tumor Thrombosis of Superior Mesenteric Vein: A Case Report

Colon cancer is very rarely accompanied by tumor thrombosis of the superior mesenteric vein (SMV). A 46-year-old patient had been diagnosed with SMV tumor thrombosis related to colon cancer without hepatic metastasis and underwent right hemicolectomy with SMV tumor thrombectomy. Tumor thrombosis was pathologically confirmed as metastatic colon cancer. There has been no recurrence for 12 months with 12 cycles of adjuvant-chemotherapy.

The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis / 한국실험동물학회지

Nonalcoholic steatohepatitis (NASH) is becoming common chronic liver disease because of the increasing global prevalence of obesity and consequently Nonalcoholic fatty liver disease (NAFLD). However, the mechanism for progression of NAFLD to NASH and then cirrhosis is not completely understood, yet. The triggering of these hepatic diseases is thought from hepatocyte injury caused by over-accumulated lipid toxicity. Injured hepatocytes release damage-associated molecular patterns (DAMPs), which can stimulate the Kupffer cells (KCs), liver-resident macrophages, to release pro-inflammatory cytokines and chemokines, and recruit monocyte-derived macrophages (MDMs). The increased activation of KCs and recruitment of MDMs accelerate the progression of NAFLD to NASH and cirrhosis. Therefore, characterization for activation of hepatic macrophages, both KCs and MDMs, is a baseline to figure out the progression of hepatic diseases. The purpose of this review is to discuss the current understanding of mechanisms of NAFLD and NASH, mainly focusing on characterization and function of hepatic macrophages and suggests the regulators of hepatic macrophages as the therapeutic target in hepatic diseases.

Optimization of scan delay for multi-phase computed tomography by using bolus tracking in normal canine kidney

This study was performed to optimize scan delays for canine kidney by using a bolus-tracking technique. In six beagle dogs, computed tomography (CT) of the kidney was performed three times in each dog with different scan delays after a bolus-tracking trigger of 100 Hounsfield units (HU) of aortic enhancement. Delays were 5, 20, 35, and 50 sec for the first scan, 10, 25, 40, and 55 sec for the second scan, and 15, 30, 45, and 60 sec for the third scan. The renal artery-to-vein contrast difference peaked at 5 sec, and the renal cortex-to-medulla contrast difference peaked at 10 sec. The renal cortex-to-medulla contrast difference approached zero at a scan delay of 30 sec after the bolus trigger. For the injection protocol used in this study, the optimal scan delay times for renal arterial, corticomedullary, and nephrographic phases were 5, 10, and 30 sec after triggering at 100 HU of aortic enhancement using the bolus-tracking technique. The bolus-tracking technique is useful in multi-phase renal CT study as it compensates for different transit times to the kidney among different animals, requires a small dose of contrast media, and does not require additional patient radiation exposure.

A Case of Small Hepatocellular Carcinoma Who Showed Complete Response by Combined Therapy of Transarterial Chemoembolization and Stereotactic Body Radiotherapy

In hepatocellular carcinoma (HCC), surgical resection or local ablation therapy is limited because of severe liver dysfunction or tumor location. Transarterial chemoembolization (TACE) has beed used widely as palliative treatment. Stereotactic Body Radiotherapy (SBRT) is a more recent and effective treatment for early stage HCC. We report a case with small HCC with complete response by TACE combined with SBRT.

Targeting Lipid Metabolic Reprogramming as Anticancer Therapeutics

Cancer cells rewire their metabolism to satisfy the demands of growth and survival, and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. Lipid metabolism is pivotal in cellular process that converts nutrients into energy, building blocks for membrane biogenesis and the generation of signaling molecules. Accumulating evidence suggests that cancer cells show alterations in different aspects of lipid metabolism. The changes in lipid metabolism of cancer cells can affect numerous cellular processes, including cell growth, proliferation, differentiation, and survival. The potential dependence of cancer cells on the deregulated lipid metabolism suggests that enzymes and regulating factors involved in this process are promising targets for cancer treatment. In this review, we focus on the features associated with the lipid metabolic pathways in cancer, and highlight recent advances on the therapeutic targets of specific lipid metabolic enzymes or regulating factors and target-directed small molecules that can be potentially used as anticancer drugs.

HLA-A*24:02/B*51:01 haplotype and lamotrigine-induced cutaneous adverse drug reactions in Koreans

Antiepileptic drugs (AEDs) have been known to induce cutaneous adverse drug reaction (cADR), ranging from a mild maculopapular eruption (MPE) to potentially life-threatening cADRs such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite studies examining mechanisms associated with human leukocyte antigen (HLA), the association between lamotrigine (LTG)-induced cADR and HLA alleles still has room to investigate. We investigated HLA-A,-B, and -C alleles in LTG-induced cADR. The medical records of four patients with LTG-induced cADR were retrospectively reviewed. All patients were treated with LTG for epilepsy. All recovered from cADR after stopping LTG treatment and receiving intensive care. HLA-A, -B, and -C genotyping was performed in all four patients using a PCR-sequence-based typing (SBT) method. Two patients had SJS, and the other two had MPE due to LTG. The range of latency to cADR after the initial LTG dose was 19–42 days. Two patients experienced cross-reactivity with other aromatic or new AEDs. Expression of the HLA-A*24:02/B*51:01 haplotype was detected in three (75%) patients with LTG-induced cADR. The other patient carried homozygous HLA-B*58:01 alleles. The results suggest that Korean individuals with the HLA-A*24:02/B*51:01 haplotype may be susceptible to LTG-induced cADR. Further investigations are necessary to confirm these findings.

Anti-cancer Effect of Luminacin, a Marine Microbial Extract, in Head and Neck Squamous Cell Carcinoma Progression via Autophagic Cell Death / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to determine whether luminacin, a marine microbial extract from the Streptomyces species, has anti-tumor effects on head and neck squamous cell carcinoma (HNSCC) cell lines via autophagic cell death. MATERIALS AND METHODS: Inhibition of cell survival and increased cell death was measured using cell viability, colony forming, and apoptosis assays. Migration and invasion abilities of head and cancer cells were evaluated using wound healing, scattering, and invasion assays. Changes in the signal pathway related to autophagic cell death were investigated. Drug toxicity of luminacin was examined in in vitro HaCaT cells and an in vivo zebrafish model. RESULTS: Luminacin showed potent cytotoxicity in HNSCC cells in cell viability, colony forming, and fluorescence-activated cell sorting analysis. In vitro migration and invasion of HNSCC cells were attenuated by luminacin treatment. Combined with Beclin-1 and LC3B, Luminacin induced autophagic cell death in head and neck cancer cells. In addition, in a zebrafish model and human keratinocyte cell line used for toxicity testing, luminacin treatment with a cytotoxic concentration to HNSCC cells did not cause toxicity. CONCLUSION: Taken together, these results demonstrate that luminacin induces the inhibition of growth and cancer progression via autophagic cell death in HNSCC cell lines, indicating a possible alternative chemotherapeutic approach for treatment of HNSCC.

Letter: The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes (Endocrinol Metab 2016;31:328-35, Cheol Ryong Ku et al.)

No abstract available.

Brief introduction to current pharmacogenomics research tools

There is increasing interest in the application of personalized therapy to healthcare to increase the effectiveness of and reduce the adverse reactions to treatment. Pharmacogenomics is a core element in personalized therapy and pharmacogenomic research is a growing field. Understanding pharmacogenomic research tools enables better design, conduct, and analysis of pharmacogenomic studies, as well as interpretation of pharmacogenomic results. This review provides a general and brief introduction to pharmacogenomics research tools, including genotyping technology, web-based genome browsers, and software for haplotype analysis.

Polycystic ovary syndrome woman with heterozygous androgen receptor gene mutation who gave birth to a child with androgen insensitivity syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is a multifactorial polygenic disorder with a broad spectrum of clinical manifestations. Although pathogenesis is still unclear, androgen receptor (AR) gene polymorphism may be one of the etiologic factors of PCOS. AR gene polymorphism has been also associated with other forms of androgen pattern diseases. We report a PCOS woman with heterozygous AR gene mutation who gave birth to a baby with andorgen insensitivity syndrome.

An unusual ultrasonographic manifestation of a fetal Ebstein anomaly

An Ebstein anomaly is a rare congenital heart defect defined by an inferior displacement of the septal and posterior leaflets of the tricuspid valve from the tricuspid annulus. This anomaly shows various ultrasonographic manifestations, thus making the prenatal diagnosis sometimes difficult. We here report a rare case of an Ebstein anomaly which was prenatally suspected as the absence of the tricuspid valve with functional pulmonary atresia because of non-visible tricuspid leaflets on an echocardiograph at 24 weeks of gestation. An emergency cesarean section was performed at 35 weeks of gestation as fetal hydrops were seen on a follow-up scan. Postnatal surgery confirmed Ebstein anomaly type-D which demonstrates an almost complete atrialization of the right ventricle with the exception of a small and infundibular component. Because of its rarity, prenatal findings of a type-D Ebstein anomaly have not been reported previously. We suggest from this first such case report that this anomaly should be considered as a possible diagnosis when the tricuspid leaflets are not well visualized.

Therapeutic effect of hepatocyte growth factor-secreting mesenchymal stem cells in a rat model of liver fibrosis

Bone marrow-derived mesenchymal stromal cells (MSCs) have been reported to be beneficial for the treatment of liver fibrosis. Here, we investigated the use of genetically engineered MSCs that overexpress hepatocyte growth factor (HGF) as a means to improve their therapeutic effect in liver fibrosis. Liver fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. HGF-secreting MSCs (MSCs/HGF) were prepared by transducing MSCs with an adenovirus carrying HGF-encoding cDNA. MSCs or MSCs/HGF were injected directly into the spleen of fibrotic rats. Tissue fibrosis was assessed by histological analysis 12 days after stem cell injection. Although treatment with MSCs reduced fibrosis, treatment with MSCs/HGF produced a more significant reduction and was associated with elevated HGF levels in the portal vein. Collagen levels in the liver extract were decreased after MSC/HGF therapy, suggesting recovery from fibrosis. Furthermore, liver function was improved in animals receiving MSCs/HGF, indicating that MSC/HGF therapy resulted not only in reduction of liver fibrosis but also in improvement of hepatocyte function. Assessment of cell and biochemical parameters revealed that mRNA levels of the fibrogenic cytokines PDGF-bb and TGF-beta1 were significantly decreased after MSC/HGF therapy. Subsequent to the decrease in collagen, expression of matrix metalloprotease-9 (MMP-9), MMP-13, MMP-14 and urokinase-type plasminogen activator was augmented following MSC/HGF, whereas tissue inhibitor of metalloprotease-1 (TIMP-1) expression was reduced. In conclusion, therapy with MSCs/HGF resulted in an improved therapeutic effect compared with MSCs alone, probably because of the anti-fibrotic activity of HGF. Thus, MSC/HGF represents a promising approach toward a cell therapy for liver fibrosis.

Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans

The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.

Epigallocatechin-3-gallate inhibits paracrine and autocrine hepatocyte growth factor/scatter factor-induced tumor cell migration and invasion

Aberrant activation of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, is involved in the development and progression of many human cancers. In the cell-based screening assay, (-)epigallocatechin-3-gallate (EGCG) inhibited HGF/SF-Met signaling as indicated by its inhibitory activity on HGF/SF-induced cell scattering and uPA activation (IC50 = 15.8 microg/ml). Further analysis revealed that EGCG at low doses specifically inhibited HGF/SF-induced tyrosine phosphorylation of Met but not epidermal growth factor (EGF)-induced phosphorylation of EGF receptor (EGFR). On the other hand, high-dose EGCG decreased both Met and EGFR proteins. We also found that EGCG did not act on the intracellular portion of Met receptor tyrosine kinase, i.e., it inhibited InlB-dependent activation of Met but not NGF-induced activation of Trk-Met hybrid receptor. This inhibition decreased HGF-induced migration and invasion by parental or HGF/SF-transfected B16F10 melanoma cells in vitro in either a paracrine or autocrine manner. Furthermore, EGCG inhibited the invasion/metastasis of HGF/SF-transfected B16F10 melanoma cells in mice. Our data suggest the possible use of EGCG in human cancers associated with dysregulated paracrine or autocrine HGF/SF-Met signaling.

The effect of implant system with reverse beveled platform design on marginal bone stress distribution / 대한치과보철학회지

PURPOSE: The purpose of this study was to investigate the effects of the surface morphology of the implant neck on marginal bone stress measured by using finite element analysis in six implant models. MATERIALS AND METHODS: The submerged type rescue implant system (Dentis co., Daegu, Korea) was selected as an experimental model. The implants were divided into six groups whose implant necks were differently designed in terms of height (h, 0.4 and 1.0 mm) and width (platform width, w = 3.34 + 2b [b, 0.2, 0.3 and 0.4 mm]). Finite element models of implant/bone complex were created using an axisymmetric scheme. A load of 100 N was applied to the central node on the top of crown in parallel with the implant axis. The maximum compression stress was calculated and compared. RESULTS: Stress concentration commonly observed around dental implants did not occur in the marginal bone around all six test implant models. Marginal bone stress varied according to the implant neck bevel which had different width and height. The stress was affected more markedly by the difference in height than in width. CONCLUSION: This result indicates that the implant neck bevel may play an important role in improving stress distribution in the marginal bone area.

Clinical outcomes of hematopoietic stem cell transplantation from HLA-matched parental donor in childhood acute leukemia / 소아과

PURPOSE: In this study, we retrospectively analyzed the clinical outcomes of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) grafted from HLA-matched parents. METHODS: Seven children with acute leukemia (4 acute lymphoblastic leukemia, 3 acute myeloid leukemia) in first complete remission received allogeneic HSCT from their respective parents at the St. Marys Hospital between April, 1999 and October, 2005. The median age of patients at transplantation was 5 years (range, 1-11 years; 2 male, 5 female) and the median age of donors was 35 years (range, 30-41 years; 5 male, 2 female). We investigated the clinical outcomes such as engraftment, acute and chronic graft-versus-host disease (GVHD), transplant-related morbidity and mortality, relapse and survival. RESULTS: Median time from transplantation to last follow-up was 69.5 months (range, 18.8-96.5 months). All patients were successfully engrafted, with a median time of 11 days (range, 10-16 days) and 26 days (range, 13-39 days) for neutrophil and platelet recovery, respectively. Grade II acute GVHD occurred in 3, and grade III acute GVHD in 1 of 7 recipients. Extensive chronic GVHD developed in 2, and limited chronic GVHD in 1 of 7 recipients. Death from transplant-related complications occurred in 1, and relapse occurred in 1 of 7 recipients. Estimated 5-year overall survival was 83+/-15%. CONCLUSION: The clinical outcomes of recipients who underwent HSCT from HLA-matched parents were comparable to those of patients who received HSCT grafted from HLA-matched sibling donors in childhood leukemia. HLA typing of parents, as well as siblings will increase the likelihood of finding an HLA-matched family donor for patients who need HSCT.